PUBLICATION
The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation
- Authors
- Veroni, C., Olla, S., Brignone, M.S., Siguri, C., Formato, A., Marra, M., Manzoli, R., Macario, M.C., Ambrosini, E., Moro, E., Agresti, C.
- ID
- ZDB-PUB-240428-8
- Date
- 2024
- Source
- Biomolecules 14(4): (Journal)
- Registered Authors
- Macario, Maria Carla, Manzoli, Rosa, Moro, Enrico
- Keywords
- aryl hydrocarbon receptor, edaravone, oligodendrocyte progenitors, zebrafish
- MeSH Terms
-
- Animals
- Antioxidants*/pharmacology
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- Cell Line, Tumor
- Edaravone*/pharmacology
- Humans
- Mice
- Molecular Docking Simulation
- Molecular Dynamics Simulation
- NF-E2-Related Factor 2*/metabolism
- Receptors, Aryl Hydrocarbon*/metabolism
- Signal Transduction*/drug effects
- Zebrafish*
- PubMed
- 38672460 Full text @ Biomolecules
Citation
Veroni, C., Olla, S., Brignone, M.S., Siguri, C., Formato, A., Marra, M., Manzoli, R., Macario, M.C., Ambrosini, E., Moro, E., Agresti, C. (2024) The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation. Biomolecules. 14(4):.
Abstract
A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets. By using high-throughput RNA-seq and biochemical experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells combined with molecular docking and molecular dynamics simulation, we here provide evidence that Edaravone triggers the activation of aryl hydrocarbon receptor (AHR) signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling transduction occurs in the zebrafish experimental model, associated with a downstream upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid cytoprotective and antioxidant actions boost increased expression of the promyelinating Olig2 protein as well as of an Olig2:GFP transgene in vivo. We therefore shed light on a still undescribed potential mechanism of action for this drug, providing further support to its therapeutic potential in the context of debilitating demyelinating conditions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping